Usher syndrome type 2A

Summary

Usher syndrome type 2A (MONDO:0010169) is a disease caused by USH2A (GenCC Definitive), with 7 cohort genes and 1 clinical trial.

At a glance

• Causal gene: USH2A (GenCC Definitive)
• Cohort genes: 7
• ClinVar variants: 2,752
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Usher syndrome type 2A
Mondo ID	MONDO:0010169
MeSH	C536490
OMIM	276901
DOID	DOID:0110838
UMLS	C1848634
MedGen	338513
GARD	0015241
Is cancer (heuristic)	no

Also known as: retinal disease in usher syndrome type IIA, modifier of · US2 · USH2A · USH2A Usher syndrome · Usher syndrome caused by mutation in USH2A · Usher syndrome type 2A · USHER syndrome, type IIA

Data availability: 2,752 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Usher syndrome › Usher syndrome type 2 › Usher syndrome type 2A

Related subtypes (2): Usher syndrome type 2C, Usher syndrome type 2D

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

228 uncertain significance, 94 likely pathogenic, 74 pathogenic/likely pathogenic, 59 likely benign, 49 pathogenic, 44 conflicting classifications of pathogenicity, 30 benign, 22 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066803	NM_206933.4(USH2A):c.2809+1G>C	LOC122152296	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070807	NM_206933.4(USH2A):c.2649del (p.Glu883fs)	LOC122152296	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1213940	NM_206933.4(USH2A):c.2431_2432del (p.Lys811fs)	LOC122152296	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1352951	NM_206933.4(USH2A):c.2779C>T (p.Gln927Ter)	LOC122152296	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143179	NM_206933.4(USH2A):c.2802T>G (p.Cys934Trp)	LOC122152296	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453703	NM_206933.4(USH2A):c.2738del (p.Cys913fs)	LOC122152296	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
166516	NM_206933.4(USH2A):c.2541C>A (p.Cys847Ter)	LOC122152296	Pathogenic	criteria provided, multiple submitters, no conflicts
100610	NM_206933.4(USH2A):c.14792-2A>G	USH2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1015542	NM_206933.4(USH2A):c.1172G>T (p.Ser391Ile)	USH2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1016214	NM_206933.4(USH2A):c.13465G>A (p.Gly4489Ser)	USH2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1024751	NM_206933.4(USH2A):c.12992A>G (p.Tyr4331Cys)	USH2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1040712	NM_206933.4(USH2A):c.14996C>T (p.Thr4999Ile)	USH2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1042201	NM_206933.4(USH2A):c.838C>T (p.Leu280Phe)	USH2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1047575	NM_206933.4(USH2A):c.14288G>A (p.Gly4763Glu)	USH2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1049672	NM_206933.4(USH2A):c.8845+2T>G	USH2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1051986	NM_206933.4(USH2A):c.4251G>T (p.Gln1417His)	USH2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1056888	NM_206933.4(USH2A):c.4124C>T (p.Ser1375Leu)	USH2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065666	NM_206933.4(USH2A):c.3828T>G (p.Tyr1276Ter)	USH2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065734	NM_206933.4(USH2A):c.14285A>G (p.Asn4762Ser)	USH2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069500	NM_206933.4(USH2A):c.9165_9168del (p.Ile3055fs)	USH2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1069548	NM_206933.4(USH2A):c.11235C>A (p.Tyr3745Ter)	USH2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1069779	NM_206933.4(USH2A):c.4251+1del	USH2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071494	NM_206933.4(USH2A):c.5737G>T (p.Glu1913Ter)	USH2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1071743	NM_206933.4(USH2A):c.7184_7194del (p.Leu2395fs)	USH2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1071761	NM_206933.4(USH2A):c.15199del (p.Ile5067fs)	USH2A	Pathogenic	criteria provided, single submitter
1073006	NM_206933.4(USH2A):c.15208G>T (p.Glu5070Ter)	USH2A	Pathogenic	criteria provided, single submitter
1074239	NM_206933.4(USH2A):c.1841-1G>A	USH2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074618	NM_206933.4(USH2A):c.11709C>G (p.Tyr3903Ter)	USH2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1074779	NM_206933.4(USH2A):c.6131C>A (p.Ser2044Ter)	USH2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074900	NM_206933.4(USH2A):c.675_678del (p.Phe225fs)	USH2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
USH2A	Definitive	Unknown	Usher syndrome type 2	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
USH2A	Orphanet:231178	Usher syndrome type 2
USH2A	Orphanet:791	Retinitis pigmentosa
CDH23	Orphanet:231169	Usher syndrome type 1
CDH23	Orphanet:2965	Prolactinoma
CDH23	Orphanet:314777	Familial isolated pituitary adenoma
CDH23	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
CDH23	Orphanet:91347	TSH-secreting pituitary adenoma
CDH23	Orphanet:96253	Cushing disease
ADGRV1	Orphanet:231178	Usher syndrome type 2
ADGRV1	Orphanet:36387	Genetic epilepsy with febrile seizure plus
PDZD7	Orphanet:231178	Usher syndrome type 2

Cohort genes → proteins

7 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
USH2A	HGNC:12601	ENSG00000042781	O75445	Usherin	gencc,clinvar
CDH23	HGNC:13733	ENSG00000107736	Q9H251	Cadherin-23	clinvar
ADGRV1	HGNC:17416	ENSG00000164199	Q8WXG9	Adhesion G-protein coupled receptor V1	clinvar
KCTD3	HGNC:21305	ENSG00000136636	Q9Y597	BTB/POZ domain-containing protein KCTD3	clinvar
PDZD7	HGNC:26257	ENSG00000186862	Q9H5P4	PDZ domain-containing protein 7	clinvar
USH2A-AS2	HGNC:40605	ENSG00000233620		USH2A antisense RNA 2	clinvar
USH2A-AS1	HGNC:40606	ENSG00000236292		USH2A antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
USH2A	Usherin	Involved in hearing and vision as member of the USH2 complex.
CDH23	Cadherin-23	Cadherins are calcium-dependent cell adhesion proteins.
ADGRV1	Adhesion G-protein coupled receptor V1	G-protein coupled receptor which has an essential role in the development of hearing and vision.
KCTD3	BTB/POZ domain-containing protein KCTD3	Accessory subunit of potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) up-regulating its cell-surface expression and current density without affecting its voltage dependence and kinetics.
PDZD7	PDZ domain-containing protein 7	In cochlear developing hair cells, essential in organizing the USH2 complex at stereocilia ankle links.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 3 · Druggable fraction: 0.29

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	2	4.9×	0.231
Antibody/Immunoglobulin	1	4.2×	0.344
GPCR	1	3.4×	0.344
Other/Unknown	3	0.8×	0.858

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
USH2A	Antibody/Immunoglobulin	yes		Laminin_G, LE_dom, FN3_dom
CDH23	Other/Unknown	no		Cadherin-like_dom, Cadherin-like_sf, Cadherin_CS
ADGRV1	GPCR	yes		GPCR_2_secretin-like, Calx_beta, EPTP
KCTD3	Scaffold/PPI	no		BTB/POZ_dom, WD40_rpt, T1-type_BTB
PDZD7	Scaffold/PPI	no		PDZ, PDZ_sf, PDZD7_HN-like
USH2A-AS2	Other/Unknown	no
USH2A-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

5 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right adrenal gland	2
right adrenal gland cortex	2
buccal mucosa cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
right lobe of liver	1
left ovary	1
right ovary	1
ventricular zone	1
left adrenal gland	1
jejunal mucosa	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
anterior cingulate cortex	1
cerebellar vermis	1
quadriceps femoris	1
bone marrow	1
liver	1
spinal cord	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
USH2A	30	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, right lobe of liver, buccal mucosa cell
CDH23	161	broad	marker	ventricular zone, left ovary, right ovary
ADGRV1	196	broad	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland
KCTD3	284	ubiquitous	marker	jejunal mucosa, right adrenal gland cortex, right adrenal gland
PDZD7	178	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
USH2A-AS2	54		yes	quadriceps femoris, anterior cingulate cortex, cerebellar vermis
USH2A-AS1	21		yes	liver, bone marrow, spinal cord

Protein interactions among cohort

Intra-cohort edges: 7.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
USH2A	2,332
ADGRV1	1,658
CDH23	1,575
PDZD7	1,317
KCTD3	1,222
USH2A-AS2	0
USH2A-AS1	0

Intra-cohort edges

A	B	Sources
ADGRV1	CDH23	string_interaction
ADGRV1	PDZD7	intact, string_interaction
ADGRV1	USH2A	string_interaction
CDH23	PDZD7	string_interaction
CDH23	USH2A	string_interaction
KCTD3	USH2A	string_interaction
PDZD7	USH2A	intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 3 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CDH23	Q9H251	6
PDZD7	Q9H5P4	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KCTD3	Q9Y597	70.88
USH2A	O75445
ADGRV1	Q8WXG9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 7 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	122.8×	0.055	ADGRV1
Sensory processing of sound	1	102.9×	0.055	CDH23
Sensory processing of sound by outer hair cells of the cochlea	1	68.0×	0.055	CDH23
Sensory processing of sound by inner hair cells of the cochlea	1	54.4×	0.055	CDH23
Sensory Perception	1	31.7×	0.075	CDH23
CDC42 GTPase cycle	1	24.1×	0.082	KCTD3
RHO GTPase cycle	1	20.0×	0.084	KCTD3
Nervous system development	1	14.3×	0.102	ADGRV1
Signaling by Rho GTPases	1	11.4×	0.104	KCTD3
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	11.2×	0.104	KCTD3
Developmental Biology	1	4.8×	0.211	ADGRV1
Signal Transduction	1	3.4×	0.267	KCTD3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
inner ear receptor cell differentiation	3	2022.2×	4e-09	USH2A, ADGRV1, PDZD7
sensory perception of light stimulus	3	1123.5×	2e-08	USH2A, CDH23, ADGRV1
sensory perception of sound	4	80.7×	5e-07	USH2A, CDH23, ADGRV1, PDZD7
establishment of protein localization	3	259.3×	1e-06	USH2A, ADGRV1, PDZD7
photoreceptor cell maintenance	3	215.1×	1e-06	USH2A, CDH23, ADGRV1
maintenance of animal organ identity	2	1348.2×	4e-06	USH2A, ADGRV1
detection of mechanical stimulus involved in sensory perception of sound	2	374.5×	5e-05	ADGRV1, PDZD7
auditory receptor cell stereocilium organization	2	337.0×	6e-05	CDH23, PDZD7
visual perception	3	47.7×	7e-05	USH2A, CDH23, ADGRV1
establishment of localization in cell	2	64.2×	0.001	USH2A, PDZD7
equilibrioception	1	481.5×	0.007	CDH23
hair cell differentiation	1	421.3×	0.007	USH2A
auditory receptor cell development	1	374.5×	0.007	PDZD7
self proteolysis	1	306.4×	0.008	ADGRV1
inner ear auditory receptor cell differentiation	1	240.7×	0.009	USH2A
nervous system process	1	240.7×	0.009	ADGRV1
obsolete cell-cell adhesion via plasma-membrane adhesion molecules	1	224.7×	0.009	CDH23
inner ear receptor cell stereocilium organization	1	168.5×	0.012	ADGRV1
calcium-dependent cell-cell adhesion	1	96.3×	0.019	CDH23
cochlea development	1	93.6×	0.019	CDH23
positive regulation of bone mineralization	1	78.4×	0.020	ADGRV1
regulation of cytosolic calcium ion concentration	1	76.6×	0.020	CDH23
inner ear development	1	74.9×	0.020	ADGRV1
cellular response to calcium ion	1	40.1×	0.036	ADGRV1
calcium ion transport	1	36.2×	0.037	CDH23
locomotory behavior	1	35.9×	0.037	CDH23
homophilic cell-cell adhesion	1	28.1×	0.046	CDH23
regulation of protein stability	1	25.1×	0.047	ADGRV1
neuron projection development	1	24.4×	0.047	CDH23
protein homooligomerization	1	24.4×	0.047	KCTD3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 7

Druggability breadth: 0 of 7 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
USH2A	0	0
CDH23	0	0
ADGRV1	0	0
KCTD3	0	0
PDZD7	0	0
USH2A-AS2	0	0
USH2A-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	2	USH2A, ADGRV1
E	Difficult family or no structure, no drug	5	CDH23, KCTD3, PDZD7, USH2A-AS2, USH2A-AS1

Undrugged target profiles

7 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
USH2A	0	—
CDH23	0	—
ADGRV1	0	—
KCTD3	0	—
PDZD7	0	—
USH2A-AS2	0	—
USH2A-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04820244	Not specified	UNKNOWN	Characterizing Rate of Progression in USHer Syndrome (CRUSH) Study